Steroidal 4,6-dien-3-ones having c6 substituents and process for preparing same



United States Patent() US. Cl. 260-23955 5 Claims ABSTRACT OF THE DISCLOSURE New steroidal-4,6-dien-3-ones having at C the group CH XR wherein X is an atom of sulfur or oxygen and R is an alkyl or aryl group containing up to 20 carbon atoms. The compounds are prepared by reacting a corresponding 6-halomethyl steroid with a metallic salt of the formula M.X.R where M is the metal and X and R have the meaning given above.

This invention is for improvements in or relating to organic compounds and has particular reference to new steroidal 4,6-dien-3-ones with an oxy(thio)methyl substituent at C In our copending applications Nos. 514,676 filed Dec. 17, 1965 and 523,247, filed Jan. 27, 1966 there are described steroidal 6-halomethyl4,6-dien-3-ones including the partial formula HaHal (H) (where Hal is F, Cl, Br and I), and processes for their preparation.

We have now made the important discovery that the halogen atom present in such steroidal 6-halomethyl-4,6- dien-3-ones including partial Formula II above may be replaced without rearrangement to give products including the partial Formula I below. This is a significant and surprising discovery as allylic structures, as will be known to those skilled in the art, often undergo structural rearrangements when submitted to substitution reactions. We have also made the discovery that some of the novel 6-substituted steroidal 4,6-dien-3-ones including the partial Formula I below can have biological properties which render them of value in the art. In addition, such 6-substituted steroidal 4,6-dien-3-ones including the partial Formula I below are of value as building blocks for the construction of novel hormonally active structures and thus have a technical importance in their own right as intermediates.

In general terms, the products of the invention can have biological properties qualitatively similar or related to the biological properties of the corresponding G-methyland 6-hydroxy(acyloxy)methyl-3-oxo-4,6-dienic steroids (our copending application S.N. 457,522 filed May 20, 1965, now issued on Mar. 26, 1968 as Patent No. 3,375,167). Thus, for example, derivatives of the 19-nortestosterone type may have claudogenic activity. Progesterone and 17u-alkyl(acyl)progesterone derivatives may have progestational and claudogenic activity. In conjunction with an oestrogen such for example as ethynyloestradiol, Inestranol, 17u-ch1orethynyl (17a-bromoethynyl) oestradiol and its 3-methyl and 3,17-dimethyl ether, 17u-trifluoropropynyl oestradiol and its 3-methyl and 3,17-dimethyl ether, 17a-trifluorovinyl oestradiol and its S-methyl and 3,17-dimethyl ether, the compounds of the present invention are of value as oral contraceptives and as anti-tumour agents in experimental assays. In addition, the compounds are of value in veterinary work for the synchronisation of oestrus and for inhibition of ovulation. Such formulations may be administered as pills, tablets and other standard pharmaceutical formulations either in the conventional 20 days/ month regimens or in sequential or serial regimens. Corticoidal structures may show some of the properties of glucocorticoids. Substituents of the type -X(CH ),,NEt may additionally confer CNS and hypocholesteraemic properties upon the structures.

According to the present invention there is provided a process for the preparation of 6-oxy(thio)methyl steroidal-4,6-dien-3-ones including the partial formula HzXR (I) where X is -O-- or -S and R is selected from the group consisting of hydrogen acyl (where acyl may be derived from aliphatic, aromatic, heterocyclic and alkaromatic moieties containing up to 20 carbon atoms), alkyl and cycloalkyl groups containing up to 20 carbon atoms, aryl and alkaryl groups containing up to 20 carbon atoms and alkylamino groups of the type (CH ),,N containing up to 12 carbon atoms, and including substituted derivatives of the above, which process comprises reacting a 6-halomethyl-4i,6dien-3-one including the partial Formula II above where Hal is F, Cl, Br or I, with a metallic salt of the formula M.X.R where M is Na, K or Li and X and R have the same meaning as above.

The process is carried out in solution or suspension in a dry organic solvent, when the following reaction occurs MXR MHalogen 0- 0- H Halogen HaXR after which the product may be isolated and standard methods described in the art.

The invention also provides new 6-oxy(thio )methyl steroidal-4,6-dien-3-ones including the partial Formula I above, where X is -O- or -S- and R is an alkyl or cycloalkyl group containing up to 20 carbon atoms, an aryl or alkaryl group containing up to 20 carbon atoms, or an alkylamino group of the type (CH ),,N containing up to 12 carbon atoms or a substitution derivative of any of the above or when X is S-, R is hydrogen or an acyl radical (where acyl is derived from aliphatic, aromatic, heterocyclic or alkaromatic moieties containing up to 20 carbon atoms).

The process of the present invention may be applied to a wide variety of steroidal compounds of the androstane, 19-norandrostane, pregnane and 19-norpregnane series which, in addition to the fi-substituted 4,6-dien-3- one present in rings A and B, may also be substituted by substituted by Hydroxyl groups and esterified and etherified derivatives thereof in such positions as C C1 C14, C C C17, C18 C C and C including such groups as 16- hydroxymethyl and the condensation products of 17aand l7a,21-glycols with carbonyl components.

Carbonyl groups in such positions as C C C C 17 C18 and 20- Carbalkoxy groups in such positions as C C C and in the side-chain.

Cyano groups in such positions as C13, C and C Alkyl groups and in particular methyl groups in such positions as C C C C17, C and ethyl groups in such positions as C Allrenyl and alkynyl groups and in particular vinyl, allyl,

ethynyl, trifluoropropynyl, trifiuorovinyl and chloroethynyl groups at C Methylene and ethylidene groups in such positions as 11 16, 16 1'7 and 17- Lactone, ether and spiroketal groups and in particular spirolactone groups including OCO-CH -CH at C etheric groups at C and bridging C and C and spiroketal groups including the sapogenin sidechain.

Fluorine atoms in particular at C Unsaturated linkages including carbon-carbon doublebonds in such positions as C C C C14 C C16 and 17(20)- The process of the present invention may be applied to the 6-halomethyl-4,6-dien-3-one compounds derived from the following steroids and their acyl derivatives:

testosterone and l9-nor derivatives thereof 2-methyltestosterone and 19-nor derivatives thereof l7a-methyltestosterone and 19-nor derivatives thereof 9 l 1 -dehydro-17a-methyltestosterone and 19-nor derivatives thereof l7a-propynyl, 17u-chloroethynyl, 17a-trifiuoropropynyl, 17u-trifluoroviny1 testosterone and 19-nor derivatives thereof 17u-acyloxyprogesterones and 19-nor derivatives thereof 9(1l)-dehydro-l7a-acyloxyprogesterones 16-methyl-17a-acyloxyprogesterones l 6-methylene-17u-acyloxyprogesterones 9 1 1 )-dehydro-l6-methylene-17a-acyloxyprogesterones l7a-acyloxy- 1 6-ethylideneprogesterones 16a,17a-dimethylmethylenedioxyprogesterone 9 l 1)-dehydr0-16a,l7a-dimethylmethylenedioxyprogesterone cortisone 1'6-methylcortisone 2 l-methylcortisone 16-methylenecortisone 16 a-hydroxy cortisone and the 1611,1704) -acetonide therehydrocortisone 16-methylhydrocortisone 21-methylhydrocortisone 1G-methylenehydrocortisone 16u-hydroxyhydrocortisone and the 1611,17) -acetonide thereof 17,21-dihydroxypregna-4,9(1l)-diene-3 ,20-dione 16-methyl-17u,2l-dihydroxypregna-4,9(l1)-dicne-3,20-

dione 2l-methyl-17a,2l-dihydroxypregna-4,9(l1)-diene-3 ,20-

dione 16-methylene-17a,21-dihydroxypregna-4,9 1 1 -diene- 3,20-dione 16a-hydroxy-1711,-2l-dihydroxypregna-4,9 1 1 )-diene- 3,20-dione and the (16,17)-acetonide thereof 2 l-hydroxypregna-4, 17 (20 -dien-3-one 1l-oxo-2 1-hydroxypregna-4, 17 (20) -dien-3-one 11,2l-dihydroxypregna-4, 1 7 (20) -dien-3-one 9 1 1 -dehydro-2l-hydroxypregna-4, 17 (20) -dien-3 -one 3-oxopregna-4, 17 (20) -dien-21-oic acid (esters) 3,1 1-dioxopregna-4, 17 (20 -dien-2 l-oic acid (esters) 1 l-hydroxy-3-oxopregna-4, 17 (20) -dien-21-oic acid (esters) 9(l1)-dehydro-3-oxopregna-4,17(20)-dien-2l-oic acid (esters) progesterone 16-methylprogesterone 1 l-oxoprogesterone 9 1 1)-dehydroprogesterone diosgenone 2 l-methylprogesterone 17a-cyano-17p-hydroxyandrost-4-en-3-one 16 (a and j3)-hydroxytestosterone and l9-nor derivatives 16-methyl-16,17-dehydroprogesterone l6-cyano-progesterone 16-carbalkoxyprogesterones 16-hydroxymethylprogesterone 3 (3 oxo 17p hydroxyandrost 4 en 17a, yl)

propionic acid testololactone The 9oz-fll10l'0 derivatives of the above llp-hydroxy and 1 l-oxo-steroids.

Following is a description by way of example of methods of carrying the invention into effect.

Example 1.17a-acetoxy-16-methylene-6-phenylthiomethylpregna-4,6-diene-3,20-dione O 0 .Me To 17fl-acetoxy-6-bromomethyl-19-norandrosta-4,6-dien-3- one, and

17,3-acetoxy-6-bromomethylandrosta-4,6-dien-3-one, and

21-acetoxy-6-bromomethy1-l 113,l7a-dihydroxypregna-4,6-

diene-3,20-dione, and

6-bromomethyl-16a,17a-isopropylidenedioxypregna-4,6-

diene-3,20-dione is productive of l7fl-acetoxy-G-phenylthiomethyl-l9-norandrosta-4,6-dien- 3-one, and

l7fl-acetoxy-6-phenylthiomethylandrosta-4,6-dien-3-one,

and

2l-acetoxy-1 1B,17a-dihydroxy-6-pheny1thiomethylpregna-4,6-diene-3,20-dione, and

16a,17u-isopropylidenedioxy'6-phenylthiornethylpregna- 4,6-diene-3,20-dione.

Example 2.-17a-acetoxy-16-methylene-6-phenoxymethylpregna-4,6-diene-3,20-dione --0Ac T0112 Me A mixture of 17a-acetoxy-6-bromomethyl-l6-methylenepregna-4,6-diene-3,20-dione (0.2 g.) and sodium phenoxide (0.15 g.) in N-methyl-Z-pyrrolidone (4 ml.) was stirred at room temperature for 5 minutes. The prodnot, isolated as described in Example 1, was crystallised from methanol to give 17a-acetoxy-16-methylene-6- phenoxy methylpregna-4,6-diene-3,20-dione as prisms, M.P. 188.5 C., [a] --72.1 (c. 0.2 in chloroform), A 220 (e 12,300) and 278 mu 23,400), and Amflexkm 272 (a 21,500) and 281 mu (6 22,900).

Similar treatment of a stoichiometric equivalent amount of 17fl-acetoxy-6-bromomethyl-l9-norandrosta-4,6-dien-3- one, and

17fl-acetoxy-6-bromomethylandrosta-4,6-dien-3-one, and

2l-acetoxy-6-bromomethy1-1 1 p, 17 a-dihydroxypre gna- 4,6-diene-3,20-dione, and

6-bromomethy1-16a, 17a-isopropylidenedioxypregna-4,6-

diene-3,20-dione is productive of 17B-acetoxy-6-phenoxymethyl-19-norandrosta4,6-dien- 3-one, and

17fl-acetoxy-6-phenoxymethylandrosta-4,6-dien-3-one,

and

21-acetoxy-1 1 3, l7a-dihydroxy-G-phenoxymethylpregna- 4,6-diene-3,20-dione, and

16a,17a-isopropylidenedioxy-6-phenoxymethylpregna- 4,6-diene-3,20-dione.

Example 3 .17a-acetoxy-16-methylene-6-(p-nitrophenoxy)methylpregna-4,6-diene-3,20-dione 17fl-acetoxy-fi-bromomethyl-l9-norandrosta-4,6-dien-3- one, and

17B-acetoxy-6-bromomethylandrosta-4,6-dien-3-one, and

2l-acetoxy-G-bromomethyl-1 1p, l7a-dihydroxypregna-4,6-

diene-3,20-dione, and

is productive of 17,3-acetoxy-6- (p-nitrophenoxy) methyl-l9-norandrosta- 4,6-dien-3-one, and

17fl-acetoxy-6- (p-nitrophenoxy)methylandrosta-4,6-dien- 3-one, and

ZI-acetoxy-l 1 p, 17 u-dihydroxy-6- (p-nitrophenoxy) methylpregna-4,6-diene-3,ZO-dione.

Example 4.17a-acetoxy-6-methoxymethyl-16-methylenepregna-4,6-diene-3,20-dione O 0 .Me

HZOMB A solution of 17ot-acetoxy-6-bromomethyl-16-methylenepregna-4,6-diene-3,20-dione (0.5 g.) in methanol (25 ml.) (containing 0.5 g. sodium methoxide) was' refluxed for 30 minutes. The product obtained on dilution with water was crystallised from aqueous methanol to give acetoxy--methoxymethyl-16-methylenepregna-4,6- diene-3,20-dione as needles, M.P. C., [a] 103.9 "(c. 0.4 in chloroform), A 281 mu (6 23,590).

Similar treatment of a stoichiometric equivalent amount of 17fl'acetoxy-6-bromomethy1-19-norandrosta-4,6-dien-3- one, and

l7fl-acetoxy-6-bromomethylandrosta-4,6-dien-3-one, and

17a-acetoxy-6-bromomethylpregna-4,6-diene-3,20-dione,

and

21-acetoxy-6bromomethy1-l 1,8,17a-dihydroxypregna- 4,6-diene-3,20-dione, and

6-bromomethyl-16a,17a-isopropylidenedioxypregna-4,6-

diene-3,20-dione and also for a reflux period of 4-6 hours, of a stoichiometric equivalent amount of 17B-acetoxy-6-chloromethyl-19-norandrosta-4,6-dien-3- one, and

17/3-acetoxy-6-chloromethylandrosta-4,6-dien-3-one, and

17a-acetoxy-6-ch1oromethylpregna-4,6-diene-3,20-dione,

and

2 l-acetoxy- 1 1,8,17a-dihydroxy-6-chloromethylpregna-4,6-

diene-3,20-dione, and

6-chloromethyl-16a,17a-isopropylidenedioxypregna-4,6-

diene-3,20-dione is productive of 17 8-acetoxy-6-methoxymethyl-19-norandrosta-4,6-dien- 3-one, and

17/3-acetoxy-6-methoxymethylandrosta-4,6-dien-3-one,

and

l7u-acetoxy-6-methoxy1nethylpregna-4,6-diene-3,20-

dione, and

2l-acetoxy-1 1 3, 17a-dihydroxy-6-methoxymethylpregna- 4,6-diene-3,20-dione, and

6-methoxymethyl-16u, 17u-iso pro pylidenedioxypre gna- 4,6-diene-3,20-dione.

Example 5.17,6-aoetoxy-6-acetoxymethylandrosta-4,6- dien-3 -one A mixture of 17p-acetoxy-6-iodomethylandrosta-4,6- dien-3-one (3.7 g.) and fused potassium acetate (15 g.) in acetone (75 ml.) was heated under reflux for 3 hours. The product, isolated as described in Example 1, was

crystallised from aqueous methanol to give 1713-acetoxy- 6-acetoxymethylandrosta-4,6-dien-3-one as prisms, M.P. 101-102 C., [a] +47 (c. 1.0 in chloroform).

Similar treatment of a stoichiometric equivalent amount of l7fl-acetoxy-6-iodomethyl-19-norandrosta-4,6-dien-3 -one,

and

l7a-acetoxy-6-iodomethylpregna-4,6-diene-3,20-dione,

and

l7a-acetoxy-6-iodomethyl-16-methylenepregna-4,6-diene- 3,20-dione, and

2l-acetoxy-1lfl,17a-dihydroxy-6-iodomethylpregna-4,6-

diene-3,20-dione, and

6-iodomethyl-16a,17a-isopropylidenedioxypregna-4,6-

diene-3 ,20-dione is productive of 17p-acetoxy-6-acetoxymethyl-l9-norandrosta-4,6-dien-3- one, and

17a-acetoxy-6-acetoxymethylpregna-4,6-diene-3,ZO-dione,

and

17a-acetoxy-6-acetoxymethyl-l6-methylenepregna-4,6-

diene-3,20-dione, and

2l-acetoxy-6-acetoxymethyl-l1,8, l7a-dihydroxypregna- 4,6-diene-3,20-dione, and

6-acetoxymethyl-16a,l7a-isopropylidenedioxypregna-4,6-

diene-3,20-dione.

Example 6.l7a-acetoxy-6-ethylthiomethyl-l6-methylenepregna-4,6-diene-3 ,20-dione 0 O.Me

-OAc TCH: Me

17,8-acetoxy-6-bromomethyl-l9-norandrosta-4,6-dien-3- one, and

l7fi-acetoxy-6-bromomethylandrosta-4,6-dien-3-one, and

17u-acetoxy-6-bromomethylpregna-4,6-diene-3,20-dione,

and

21-acetoxy-6-bromomethyl-11p,17a-dihydroxypregna-4,6-

diene-3,20-dione, and

6-bromomethyl-16a,17a-isopropylidenedioxypregna-4,6-

diene-3,20-dione is productive of 175-acetoxy-G-ethylthiomethyl-l9-norandrosta-4,6-dien- 3-one, and 17 B-acetoxy-G-ethylthiomethylandrosta-4,6-dien-3-one,

and l7a-acetoxy-6-ethylthiomethylpregna-4,6-diene-3,20-

dione, and 21-acetoxy-11B,l7a-dihydroxy-6-ethylthiomethylpregna- 4,6-diene-3,20-dione, and 6-ethylthiomethyl-16a,17u-isopropylidenedioxypregna- 4,6-diene-3,20-di0ne.

8 Example 7.16a, l7a-isopropylidenedioxy-6-(p-nitrophenoxy) rnethylpregna-4,6-diene-3 ,20-dione CO.Me

A mixture of 6-bromomethyl-l6a,17a-isopropylidenedioxypregna-4,6-diene-3,ZO-dione (200 mg.) and sodium pnitrophenoxide (0.35 g.) in N-methyl-Z-pyrrolidone (4 ml.) was stirred for 1 hour at room temperature. The product was isolated with ether and crystallised from ethanol to give 16a,l7rx-isopropylidenedioxy-6-(p-nitrophenoxy)methylpregna-4,6-diene-3,20-dione, as needles, M.P. 227 C., [u] +93.5 (c. 0.8 in chloroform), a 284 my. (e,30,900).

Example 8.l7a-acetoxy-6-(p-nitrophenoxy)methylpregna-4,6-diene-3,20-dione A mixture of 17u-acetoxy-6-bromomethylpregna-4,6-diene-3,20-dione (200 mg.) and sodium p-nitrophenoxide (0.35 g.) in N-methyl-Z-pyrrolidone (4 ml.) was stirred for 1 hour at room temperature. The mixture was poured into water and the product isolated with a mixture of dichloromethane and ether. crystallisation from ethyl acetate gave 17a-acetoxy-6-(p-nitrophenoxy-methylpregna- 4,6-diene-3,20-dione, M.P. 241-243 C., [a] |34 (c. 0.2 in chloroform), A 283 my. (5, 30,200).

Example 9.-17a-aectoxy-6-phenoxymethylpregna-4,6- diene-3,20-dione O 0 .Mo

A mixture of 17a-acetoxy-6-bromomethylpregna-4,6-diene-3,20-dione (200 mg.) and sodium phenoxide (200 mg.) in N-methyl-2-pyrrolidone (4 ml.) was stirred for 1 hour at room temperature. The product was isolated with ether, and crystallised from ethanol to give 17u-acetoxy- 6 phenoxymethylpregna-4,6-diene-3,20-dione, as plates, M.P. 177 C., [a] +31 (c. 0.2 in chloroform), A 278 m (6, 23,100).

9 Example 10.17a-acetoxy-6-phenylthiomethylpregna- 4,6-diene-3,20-dione H2.S.CsH

Example 1 1.l7ot-acetoxy-6-(p-pheny1phenoxy)methylpregna-4,6-diene-3,20dione O 0 .Me

A mixture of l7a-acetoxy-6-bromomethylpregna-4,6- diene-3,20-dione (200 mg.) and sodium o-phenylphenoxide (200 mg.) in N-methyl-2-pyrrolidone (2 ml.) was stirred for 2 hours at room temperature. The mixture was poured into water and the product isolated with a mixture of dichloromethane and ether. Crystallisation from acetone gave 17a-acetoxy-6-(o-phenylphenoxy)methylpreg- 10 na-4,6-diene-3,20-dione as needles, M.P. 215-2l6 C., [a] +17 (c. 0.7 in chloroform), Amax, 282 m (6, 22,500).

We claim: 1. A process for the preparation of 6-oxy-(thio)methyl steroidal-4,6-dien-3-ones having the formula HzXR (I) where X is O- or S-, R is selected from the group consisting of alkyl and aryl groups containing up to 20 carbon atoms, and A is the remainder of the steroid molecule, which process comprises reacting a 6-halomethyl 4,6-dien-3-one including the partial formula where Hal is Cl, Br, or I, with a metallic salt of the formula M.X.R where M is Na, K or Li and A, X and R have the same meaning as above.

2. A process as claimed in claim 1 wherein the process is carried out in solution or suspension in a dry organic solvent.

3. A compound selected from the group consisting of pregna-4,6-diene-3-, 20-dione and androsta-4,6-dien-3-one derivatives having at C the group CH XR wherein, X is an atom of oxygen or sulfur, and R is an alkyl or aryl group containing up to 20 carbon atoms.

4. 17a acetoxy 16 methylene-6-phenylthiomethylpregna-4,6-diene-3,20-dione.

5. 17a acetoxy-16-methylene-6-phenoxymethylpregna- 4,6-diene-3,20-dione.

6. a acetoxy 16 methylene 6-(p-nitrophenoxy)- methylpregna-4,6-diene-3,20-dione.

7. 17a acetoxy 6 methoxymethyl-l6-methylenepregna-4,6-diene-3,20-dione.

8. 17B acetoxy 6 acetoxymethylandrosta-4,6-dien- 3-one.

9. 17a acetoxy 6 ethylthiomethyl 16-methylenepregna-4,6-diene-3,20-dione.

10. 16oz,17u isopropylidenedioxy 6 (p-nitrophenoxy)methylpregna-4,6-diene-3,20-dione.

11. 17a acetoxy 6 (p-nitrophenoxy)methylpregna- 4,6-diene-3,20-dione.

12. 17oz acetoxy 6 phenoxymethylpregna-4,6-diene- 3,20-dione.

13. 17a acetoxy 6 phenylthiomethylpregna-4,6-diene3,20-dione.

14. 170: acetoxy 6 -(p-phenylphenoxy)methylpregna- 4,6-diene-3,20-dione.

15. 17a acetoxy 6 (o-phenylphenoxy)methylpregna-4,6-diene-3,20-dione.

References Cited UNITED STATES PATENTS 3/1966 Bowers et al.

HENRY A. FRENCH, Primary Examiner. 

